This is a two year Pilot Project to develop novel technology to deliver RNAi to brain to reduce the level of targeted proteins. This project will target the alpha subunit of the ionotropic glycine receptor (GLRA1). RNAi is a form of gene knockdown that has recently been adapted for use in the brain. Viral vectors containing shRNAs or naked siRNAs are injected directly into the brain, but their effects are only exerted around the injection site. We propose to develop a delivery system consisting of a recombinant lentiviral vector pseudotyped with rabies virus glycoprotein (RVG) for short hairpin RNAs. This method will exploit the tropism of the rabies virus envelope protein which is thought to use nACH receptors and NCAM as sites of viral entry in the CMS. Administration of these viral particles to mice will produce CNS-wide gene knockdown and presumably a change in behavioral phenotype (which will be studied in the animal core).